Elucidation of the Active Conformation of Vancomycin Dimers with Antibacterial Activity against Vancomycin‐Resistant Bacteria

Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin‐resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC‐VV‐linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin‐resistant Staphylococcus aureus in vitro. In addition, double‐disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin‐resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin‐resistant strains.     

Popcorn‐Shaped Magnetic Core–Plasmonic Shell Multifunctional Nanoparticles for the Targeted Magnetic Separation and Enrichment,Label‐Free SERS Imaging,and Photothermal Destruction of Multidrug‐Resistant Bacteria

Over the last few years, one of the most important and complex problems facing our society is treating infectious diseases caused by multidrug‐resistant bacteria (MDRB), by using current market‐existing antibiotics. Driven by this need, we report for the first time the development of the multifunctional popcorn‐shaped iron magnetic core–gold plasmonic shell nanotechnology‐driven approach for targeted magnetic separation and enrichment, label‐free surface‐enhanced Raman spectroscopy (SERS) detection, and the selective photothermal destruction of MDR Salmonella DT104. Due to the presence of the “lightning‐rod effect”, the core–shell popcorn‐shaped gold‐nanoparticle tips provided a huge field of SERS enhancement. The experimental data show that the M3038 antibody‐conjugated nanoparticles can be used for targeted separation and SERS imaging of MDR Salmonella DT104. A targeted photothermal‐lysis experiment, by using 670 nm light at 1.5 W cm^?2 for 10 min, results in selective and irreparable cellular‐damage to MDR Salmonella. We discuss the possible mechanism and operating principle for the targeted separation, label‐free SERS imaging, and photothermal destruction of MDRB by using the popcorn‐shaped magnetic/plasmonic nanotechnology.     

Di‐N‐Methylation of Anti‐Gram‐Positive Aminoglycoside‐Derived Membrane Disruptors Improves Antimicrobial Potency and Broadens Spectrum to Gram‐Negative Bacteria

The effect of di‐N‐methylation of bacterial membrane disruptors derived from aminoglycosides (AGs) on antimicrobial activity is reported. Di‐N‐methylation of cationic amphiphiles derived from several diversely structured AGs resulted in a significant increase in hydrophobicity compared to the parent compounds that improved their interactions with membrane lipids. The modification led to an enhancement in antibacterial activity and a broader antimicrobial spectrum. While the parent compounds were either modestly active or inactive against Gram‐negative pathogens, the corresponding di‐N‐methylated compounds were potent against the tested Gram‐negative as well as Gram‐positive bacterial strains. The reported modification offers a robust strategy for the development of broad‐spectrum membrane‐disrupting antibiotics for topical use.     

Combating Multidrug‐Resistant Bacteria: Current Strategies for the Discovery of Novel Antibacterials

The introduction of effective antibacterial therapies for infectious diseases in the mid‐20th century completely revolutionized clinical practices and helped to facilitate the development of modern medicine. Many potentially life‐threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chemistry.     

A β‐Lactamase‐Imprinted Responsive Hydrogel for the Treatment of Antibiotic‐Resistant Bacteria

Antibiotics play important roles in infection treatment and prevention. However, the effectiveness of antibiotics is now threatened by the prevalence of drug‐resistant bacteria. Furthermore, antibiotic abuse and residues in the environment cause serious health issues. In this study, a stimuli‐responsive imprinted hydrogel was fabricated by using β‐lactamase produced by bacteria for deactivating antibiotics as the template molecule. The imprinted hydrogel could initially trap β‐lactamase excreted by drug‐resistant bacteria, thus making bacteria sensitive to antibiotics. After the bactericidal treatment, the “imprinted sites” on the hydrogel could be reversibly abolished with a temperature stimulus, which resulted in the reactivation of β‐lactamase to degrade antibiotic residues. We also present an example of the use of this antibacterial design to treat wound infection.     

Anticancer Potency and Multidrug‐Resistant Studies of Self‐Assembled Arene–Ruthenium Metallarectangles

A suite of three tetraruthenium metallacycles have been obtained from [2+2] self‐assemblies between N,N′‐Di‐(4‐pyridyl)‐1,4,5,8‐naphthalenetetracarbo–xydiimide ( 4 ) and one of the three dinuclear arene ruthenium clips, (η⁶‐p‐iPrC₆H₄Me)₂Ru₂(OO∩OO)][OTf]₂ (OO∩OO=oxalate 1 , 2,5‐dioxydo‐1,4‐benzoquinonato (dobq) 2 , 5,8‐dihydroxy‐1,4‐naphthaquinonato (donq) 3 ; OTf=triflate). All complexes were isolated in good yield (>85 %) as triflate salts and were fully characterized by using ¹H NMR and UV/Vis spectroscopies, and high‐resolution electrospray mass spectrometry. A single crystal of the metallarectangle 5 was suitable for X‐ray diffraction structural characterization. The biological activities of the metallacycles were determined by using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assays, establishing their in vitro anticancer properties. Our results show that for the AGC (gastric cancer) cell lines, the cytotoxicity of (donq)‐containing SCC 7 exceeds that of cisplatin, which was used as a control. For HCT15 (colon cancer) cell lines, the cytotoxicity is comparable to both cisplatin and doxorubicin. An in vivo hollow fiber model was used to show growth‐inhibitory activity against HCT15 and image‐based cytometry experiments indicated that 7 induced apoptosis as the mode of cell death. Complex 7 also showed significant antitumor activity for multidrug‐resistant HCT15/CLO2 cell lines, for which doxorubicin was ineffective.     

Donor‐Bound Glycosylation for Various Glycosyl Acceptors: Bidirectional Solid‐Phase Semisynthesis of Vancomycin and Its Derivatives

The glycosidation of a polymer‐supported glycosyl donor, N‐phenyltrifluoroacetimidate, with various glycosyl acceptors is reported. The application of the polymer‐supported N‐phenyltrifluoroacetimidate is demonstrated in the synthesis of vancomycin derivatives. 2‐O‐[2‐(azidomethyl)benzoyl]glycosyl imidate was attached to a polymer support at the 6‐position by a phenylsulfonate linked with a C13 alkyl spacer. Solid‐phase glycosidation with a vancomycin aglycon, selective deprotection of the 2‐(azidomethyl)benzoyl group, and glycosylation of the resulting 2‐hydroxy group with a vancosamine unit were performed. Nucleophilic cleavage from the polymer support with acetate, chloride, azido, and thioacetate ions provided vancomycin derivatives in pure form after simple purification. The semisynthesis of vancomycin was achieved by deprotection of the acetate derivative.     

Multivalent Aptamer–RNA Conjugates for Simple and Efficient Delivery of Doxorubicin/siRNA into Multidrug‐Resistant Cells

Multivalent aptamer–siRNA conjugates containing multiple mucin‐1 aptamers and BCL2‐specific siRNA are synthesized, and doxorubicin, an anthracycline anticancer drug, is loaded into these conjugates through intercalation with nucleic acids. These doxorubicin‐incorporated multivalent aptamer–siRNA conjugates are transfected to mucin‐1 overexpressing MCF‐7 breast cancer cells and their multidrug‐resistant cell lines. Doxorubicin‐incorporated multivalent aptamer–siRNA conjugates exert promising anticancer effects, such as activation of caspase‐3/7 and decrease of cell viability, on multidrug‐resistant cancer cells because of their high intracellular uptake efficiency. Thus, this delivery system is an efficient tool for combination oncotherapy with chemotherapeutics and nucleic acid drugs to overcome multidrug resistance.

     

Mixed Micelles for Targeted and Efficient Doxorubicin Delivery to Multidrug‐Resistant Breast Cancer Cells

For efficient treatment of multidrug‐resistance (MDR) breast cancer cells, design of biocompatible mixed micelles with diverse functional moieties and superior stability is needed for targeted delivery of chemical drugs. In this study, polypropylene glycol (PPG)‐grafted hyaluronic acid (HA) copolymers (PPG‐g‐HA) are used to make mixed micelles with different amounts of pluronic L61, named PPG‐g‐HA/L61 micelles. Optimized PPG‐g‐HA/L61 micelles with 3% pluronic L61 exhibit great stability in aqueous solution, superior biocompatibility, and significantly increased uptake into MCF‐7 MDR cells via HA–CD44‐specific interactions when compared to free doxorubicin (DOX) and other types of micelles. In addition, DOX in PPG‐g‐HA/L61 micelles with 3% pluronic L61 have toxicity in MCF‐7 MDR cells but significantly lower toxicity in fibroblast L929 cells compared to free DOX. Thus, PPG‐g‐HA/L61 micelles with 3% pluronic L61 content can be a promising nanocarrier to overcome MDR and release DOX in a hyaluronidase‐sensitive manner without any toxicity to normal cells.

     

Proanthocyanin-Capped Biogenic TiO2 Nanoparticles with Enhanced Penetration,Antibacterial and ROS Mediated Inhibition of Bacteria Proliferation and Biofilm Formation: A Comparative Approach

Biofunctionalized TiO₂ nanoparticles with a size range of 18.42±1.3 nm were synthesized in a single-step approach employing Grape seed extract (GSE) proanthocyanin (PAC) polyphenols. The effect of PACs rich GSE corona was examined with respect to 1) the stability and dispersity of as-synthesized GSE-TiO₂-NPs, 2) their antiproliferative and antibiofilm efficacy, and 3) their propensity for internalization and reactive oxygen species (ROS) generation in urinary tract infections (UTIs) causing Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus saprophyticus strains. State-of-the-art techniques were used to validate GSE-TiO₂-NPs formation. Comparative Fourier transformed infrared (FTIR) spectral analysis demonstrated that PACs linked functional -OH groups likely play a central role in Ti⁴⁺ reduction and nucleation to GSE-TiO₂-NPs, while forming a thin, soft corona around nascent NPs to attribute significantly enhanced stability and dispersity. Transmission electron microscopic (TEM) and inductively coupled plasma mass-spectroscopy (ICP-MS) analyses confirmed there was significantly (p<0.05) enhanced intracellular uptake of GSE-TiO₂-NPs in both Gram-negative and -positive test uropathogens as compared to bare TiO₂-NPs. Correspondingly, compared to bare NPs, GSE-TiO₂-NPs induced intracellular ROS formation that corresponded well with dose-dependent inhibitory patterns of cell proliferation and biofilm formation in both the tested strains. Overall, this study demonstrates that -OH rich PACs of GSE corona on biogenic TiO₂-NPs maximized the functional stability, dispersity and propensity of penetration into planktonic cells and biofilm matrices. Such unique merits warrant the use of GSE-TiO₂-NPs as a novel, functionally stable and efficient antibacterial nano-formulation to combat the menace of UTIs in clinical settings.     

A Multifunctional Subphthalocyanine Nanosphere for Targeting,Labeling, and Killing of Antibiotic‐Resistant Bacteria

Developing a material that can combat antibiotic‐resistant bacteria, a major global health threat, is an urgent requirement. To tackle this challenge, we synthesized a multifunctional subphthalocyanine (SubPc) polymer nanosphere that has the ability to target, label, and photoinactivate antibiotic‐resistant bacteria in a single treatment with more than 99 % efficiency, even with a dose as low as 4.2 J cm^?2 and a loading concentration of 10 nM . The positively charged nanosphere shell composed of covalently linked SubPc units can increase the local concentration of photosensitizers at therapeutic sites. The nanosphere shows superior performance compared to corresponding monomers presumably because of their enhanced water dispersibility, higher efficiency of singlet‐oxygen generation, and phototoxicity. In addition, this material is useful in fluorescence labeling of living cells and shows promise in photoacoustic imaging of bacteria in vivo.     

A Far‐Red Fluorescent DNA Binder for Interaction Studies of Live Multidrug‐Resistant Pathogens and Host Cells

Transgene expression of green fluorescent protein (GFP) has facilitated the spatiotemporal investigation of host–pathogen interactions; however, introduction of the GFP gene remains challenging in drug‐resistant bacteria. Herein, we report a novel far‐red fluorescent nucleic acid stain, 6‐TramTO‐3 , which efficiently labels bacteria through a DNA binding mode without affecting growth and viability. Exemplarily, we stained Klebsiella pneumoniae, a major threat to hospitalized patients, and deciphered divergent interaction strategies of antibiotic‐resistant and antibiotic‐sensitive Klebsiella strains with immune cells. 6‐TramTO‐3 constitutes an off‐the‐shelf reagent for real‐time analysis of bacterial infection, including strains for which the use of genetically encoded reporters is not feasible. Eventually, our approach may aid the development of strategies to combat a major worldwide health threat: multidrug‐resistant bacteria.     

Mechanisms,Anti-Quorum-Sensing Actions,and Clinical Trials of Medicinal Plant Bioactive Compounds against Bacteria: A Comprehensive Review

Bacterial strains have developed an ability to resist antibiotics via numerous mechanisms. Recently, researchers conducted several studies to identify natural bioactive compounds, particularly secondary metabolites of medicinal plants, such as terpenoids, flavonoids, and phenolic acids, as antibacterial agents. These molecules exert several mechanisms of action at different structural, cellular, and molecular levels, which could make them candidates or lead compounds for developing natural antibiotics. Research findings revealed that these bioactive compounds can inhibit the synthesis of DNA and proteins, block oxidative respiration, increase membrane permeability, and decrease membrane integrity. Furthermore, recent investigations showed that some bacterial strains resist these different mechanisms of antibacterial agents. Researchers demonstrated that this resistance to antibiotics is linked to a microbial cell-to-cell communication system called quorum sensing (QS). Consequently, inhibition of QS or quorum quenching is a promising strategy to not only overcome the resistance problems but also to treat infections. In this respect, various bioactive molecules, including terpenoids, flavonoids, and phenolic acids, exhibit numerous anti-QS mechanisms via the inhibition of auto-inducer releases, sequestration of QS-mediated molecules, and deregulation of QS gene expression. However, clinical applications of these molecules have not been fully covered, which limits their use against infectious diseases. Accordingly, the aim of the present work was to discuss the role of the QS system in bacteria and its involvement in virulence and resistance to antibiotics. In addition, the present review summarizes the most recent and relevant literature pertaining to the anti-quorum sensing of secondary metabolites and its relationship to antibacterial activity.     

A Mechanochemical Approach to Nanocomposites Using Single‐Wall Carbon Nanotubes and Poly(L‐lysine)

A simple method to fabricate polymer nanocomposites with single‐walled carbon nanotubes is reported, in which the nanotubes were reacted with poly(L ‐lysine) by using high‐speed vibration milling. The nanocomposites obtained were characterized by Fourier transform infrared (FT‐IR), UV–Vis spectroscopy, and thermogravimetric methods. The morphology as well as the dispersion of the carbon nanotubes were determined by scanning and transmission electron microscopy.

     

Simultaneous Capture,Detection, and Inactivation of Bacteria as Enabled by a Surface‐Enhanced Raman Scattering Multifunctional Chip

Herein, we present a multifunctional chip based on surface‐enhanced Raman scattering (SERS) that effectively captures, discriminates, and inactivates pathogenic bacteria. The developed SERS chip is made of a silicon wafer decorated with silver nanoparticles and modified with 4‐mercaptophenylboronic acid (4‐MPBA). It was prepared in a straightforward manner by chemical reduction assisted by hydrogen fluoride etching, followed by the conjugation of 4‐MPBA through Ag? S bonds. The dominant merits of the fabricated SERS chip include excellent reproducibility with a relative standard deviation (RSD) value smaller than 11.0 %, adaptable bacterial‐capture efficiency (ca. 60 %) at low concentrations (500–2000 CFU mL^?1), a low detection limit (down to a concentration of 1.0×10² cells mL^?1), and high antibacterial activity (an antibacterial rate of ca. 97 %). The SERS chip enabled sensitive and specific discrimination of Escherichia coli and Staphylococcus aureus from human blood.     

A Triptycene‐Based Approach to Solubilising Carbon Nanotubes and C60

We describe herein the synthesis of a triptycene‐based surfactant designed with the ability to solubilise single‐walled carbon nanotubes (SWNTs) and C₆₀ in water through non‐covalent interactions. Furthermore, an amphiphilic naphthalene‐based surfactant with the same ability to solubilise SWNTs and C₆₀ has also been prepared. The compounds synthesised were designed with either two ionic or non‐ionic tails to ensure a large number of supramolecular interactions with the solvent, thereby promoting strong solubilisation. The surfactants produced stable suspensions in which the SWNTs are dispersed and the surfactant/SWNT complexes formed are stable for more than one year. UV/Vis/NIR absorption spectroscopy, TEM and AFM were employed to probe the solubilisation properties of the dispersion of surfactants and SWNTs in water.     

A Concise Approach to the Synthesis of L‐ and Z)‐Deoxyribose

D‐Deoxyribose, the basic structure unit of DNA, and its antipode L‐deoxyribose were concisely synthesized from easily available D‐ and L‐glyceralaldehydes using a known convenient diastereoselective propargylation as the key step.